Genetics

Dynamic consent has the potential to facilitate personalised medicine delivering on its goals

Liza Goncharov · Hanna Suominen · Matthew Cook

As the number of requests for raw genomic data increases, policies and protocols reflecting the perspectives of clinicians, patients, researchers and research participants are required

Jane L Nielsen · Carolyn Johnston · Tracey O'Brien · Vanessa J Tyrrell

The estimated prevalence of hereditary pancreatitis in South Australia is higher than in Europe, particularly among Indigenous young people

Denghao Wu · Tristan J Bampton · Hamish S Scott · Alex Brown · Karin Kassahn · Christopher Drogemuller · Sunita MC De Sousa · David Moore · Thuong Ha · John WC Chen · Sanjeev Khurana · David J Torpy · Toni Radford · Richard Couper · Lyle Palmer · P Toby Coates

Australia to take a world-first step towards offering preventive DNA screening through the public health care system

For the DNA Screen Investigator Group†

Current genetic testing guidelines may overlook patients with actionable mutations in high risk breast and ovarian cancer predisposition genes

Dilanka L De Silva · Paul A James · G Bruce Mann · Geoffrey J Lindeman

Despite limits to its clinical value, the potential benefi ts for women should not be overlooked

Belinda E Kiely · Annabel Goodwin

Australia has the clinical and scientific expertise to introduce mitochondrial donation in a highly regulated environment, but requires changes in legislation to adopt this innovative technology

Marie A Dziadek · Carolyn M Sue

A virtual brain bank could maximise the potential of brain donation by extending the core physical bank to include existing repositories of clinical tissues and data Brain banking, whereby post mortem brains are harvested, processed, stored and made available to facilitate health and medical research, provides scientists with an unparalleled resource for macroscopic, microscopic and molecular investigations into many brain conditions. The human brain is seen as the final frontier of scientific research, with many cognitive processes and neurological diseases exclusively manifesting in humans. This uniqueness has been postulated as an explanation for why many brain disease drug leads do not progress past the acknowledged “valley of death” whereby success in animals is not translated to human clinical trials.1 For many brain researchers, human post mortem tissue is therefore preferred or essential for their investigations. The importance and utility of whole brain banking was recently demonstrated by a collection of articles in the Handbook of Clinical Neurology.2 In particular, Zielke and Mash, in a wide ranging review of bank management and operations, posed the question of whether “the value of the brain can be enhanced by collecting other tissues”.3 Here we make the case for the affirmative by describing how brain banking can, by aligning with broader biobanking initiatives, enhance the value of brain tissue for both current and “future patients and society”3. State of play Biobanks that collect tissue other than brains are typically embedded in clinical workflows, whereby collection and characterisation of residual tissue for biobanking takes place in parallel with tissue required for clinical purposes. However, in our experience in Australia, brain removal is not routinely included as part of an autopsy or post mortem examination. Autopsies themselves are now uncommon, even within the forensic setting;4 reasons for this are varied and include advances in ante mortem diagnosis propelled by imaging technologies, a belief that autopsy reports fuel malpractice lawsuits, logistic issues, and poor reimbursement rates for pathologists.5 It is now common in Australia for pathology specialists to complete their training without having conducted a post mortem examination, with the future pathology workforce destined to be demarcated into those who have and have not received training to conduct an autopsy. Today, brain removal is largely confined to the setting of brain donor programs, established to recruit and clinically characterise donors with specific diseases and, more rarely, controls.4 One reason for the decline in clinical and forensic autopsies performed is the increasing quality of modern imaging techniques.6 Similarly, ‐omic approaches, particularly metabolomics, for obtaining brain‐specific information7,8 are being increasingly applied to clinically available tissues such as serum and cerebrospinal fluid. Brain organoids developed from patient‐derived stem cells are also a promising in vitro model.9 At present, neuropathological confirmation of disease provides a “ground truth” but over time, refinement of imaging, peripheral biomarkers and in vitro models could diminish the importance of whole brain banking in isolation. For brain donor programs, brain removal logistics are often complex and costly, with reliance on in‐kind support from funeral directors, clinicians and mortuary staff. After tissue harvesting, brains require specialist processing expertise and large storage areas, resulting in increased labour and space costs. The timing and finality of brain removal can also have an impact on the collection of longitudinal clinical data, which may require medical records departmental input and/or facilitation by family members. The predicted rise in the morbidity and mortality of dementia and reported increases in the prevalence of mental health in Australia provide convincing evidence of the need for research into risk factors and therapies for neurological diseases. Currently, whole brain banks typically characterise and collect in the vicinity of 1000 donors. Cohorts of pathologically confirmed cases and controls tend to be an order of magnitude smaller than that required to efficiently carry out genetic analyses such as genome‐wide association studies. In the future, even larger cohorts will be required to examine the probable gene–environment interactions that confer risk for many sporadic brain diseases.10 We propose a novel brain banking strategy that maximises the potential of brain donation by extending the core physical bank to include existing repositories of clinical tissues and data, creating a virtual brain bank. This would not only benefit brain researchers but also researchers investigating potential interactions between the brain and other vital organs. A next‐generation solution Rather than competing with alternative technologies, a next‐generation (virtual) brain bank could incorporate these technologies into a suite of products offered to researchers. Although brain donor programs already strive to maximise the clinical and demographic information available for each participant (Box 1), an integrated brain bank could extend their involvement to more comprehensive clinical data collection, generation and analysis. This would make samples and derivatives such as serum, DNA, images and genetic/‐omic data available for researchers, in addition to brain tissue.3 We suggest extending this approach beyond tissues from donors themselves to include collaborations with existing brain‐specific clinical tissue banks such as the National Centralized Repository for Alzheimer’s Disease and Related Dementias (NCRAD). The NCRAD stores clinical non‐brain tissue samples from over 90 000 participants — in the order of two degrees of magnitude larger than the number of donors in most brain banks (Box 2). These samples have been subjected to multi‐omic analyses, and with associated imaging data have provided key insights into Alzheimer disease.11 Their level of analysis on ante mortem samples would allow an unprecedented depth of clinicopathological correlations if a subset of participants consented to brain autopsy. Extending this scenario, a next‐generation brain bank could be integrated into multipurpose biobanking initiatives. The size and intensive phenotyping within prospective cohort studies such as the UK Biobank (https://www.ukbiobank.ac.uk/), which hosts 500 000 participants, offers data on a rich source of age‐related brain diseases over time. Furthermore, there is already genetic, neuroimaging and neuropsychological testing data available from neurologically normal volunteers, enabling brain bank personnel to use their skills and expertise to provide risk factor insights as well as directing subsequent mechanistic studies in post mortem brain tissue (Box 2). In this scenario, the brain bank could remain responsible for the characterisation and provision of brain‐related tissue and data, but be just one component in an integrated resource that characterises the lifespan of an individual donor. This would not only allow brain banks to contribute to research on brain diseases for living patients, but would also create bi‐directional synergies with researchers of other diseases; that is, “brain and body” biobanking. For example, diabetes has been shown to have a central component,12 dementia and cardiovascular disease share common risk factors,13 and there are fascinating inverse associations between neurodegenerative diseases and cancer.14 In the integrated biobank envisaged, a dynamic consent model could be employed whereby an initial permission to contact could be followed by consent for provision of data and clinical samples, and eventually by consent for post mortem brain donation. A dynamic consent model also encourages deeper participant engagement. Ultimately, only a small proportion of participants are likely to become whole brain donors (Box 2), meaning direct clinicopathological correlations will always be limited. However, the workflow of a more inclusive brain and body banking model would enable complementary resources to be offered to a broader range of scientists. The 2016 National Research Infrastructure Roadmap15 recommended investment into collaborative and effective biobanking in Australia, with the government response recommending a national biobank scoping study. One possible outcome of a biobank scoping study is for the federal government to re‐engage in funding single or multi‐disease initiatives on a state or national basis. For example, the 45 and Up Study that follows approximately 250 000 middle aged community volunteers in New South Wales is a data‐linked cohort study with the potential to underpin such a brain and body biobank.16 Importantly, data linkage with routinely collected clinical and administrative data in the Australian health system gives further credence to the integration of brain banking with state or nation‐wide biobanking initiatives where clinical laboratory test results, medication history and comorbidity data can validate or extend self‐reported information. A multi‐focus bank or any research infrastructure becomes challenging to fund after initial investments. The integration of expertise across diseases and an intramural science program that kick starts traditional collaborations and commercial opportunities should have a favourable impact on the value proposition for current and future investors. Governance will be the key ingredient for success, but as with the multi‐focal nature of the proposed biobank, the board, science advisory committee and management team should look outside traditional professional boundaries for their representation. Certainly, a modern biobank needs buy‐in from state and federal health authorities, but it should also include representatives from the business community, patient advocacy groups and health practitioners to promote bi‐directional communication to known and as yet unrealised stakeholders. It has been suggested that to be most effective, biobanking needs to change its modus operandi from a static operation that banks tissue indefinitely to one that is actively involved in the research process — a so‐called biolibrary. By integrating with wider biobanking initiatives, next‐generation brain banks can contribute to the clinical, pathological and clinicopathological characterisation of a range of tissues and data for researchers of all disease interests. Importantly, a virtual brain bank or brain and body biolibrary will create future research synergies that otherwise would not be achieved. Box 1 – Schematic diagram showing a typical brain bank operating in conjunction with a brain donor program for a specific disease K = 1000. Box 2 – Schematic diagram of an integrated brain biobank with capacity to combine with and leverage wider biobanking endeavours (ideally suited to sporadic brain diseases with multi‐factorial aetiologies) K = 1000.

Amanda Rush · Greg T Sutherland

To the Editor: Hereditary cancer predisposition syndromes (HCPS) account for at least 10% of paediatric cancers.1 Li‐Fraumeni syndrome (LFS) is a dominant HCPS caused by mutations in the TP53 gene and is associated with an 80–90% lifetime risk of cancer, commencing in infancy.2 Children of affected individuals are at 50% risk of inheriting the family mutation. Surveillance programs, involving clinical review and medical imaging, are being used in paediatric populations with HCPS, as significantly higher overall survival is reported with early tumour detection.3 In 2018, the Paediatric Surveillance Clinic was established at Perth Children’s Hospital to provide surveillance for asymptomatic children with, or at 50% risk of developing, LFS and with other HCPS, and to address the needs of their families. Families with at‐risk children can choose to attend the clinic, allowing them to receive information, support and sufficient time to make a decision regarding genetic testing. The quarterly clinic is in a general paediatric setting and offers surveillance for mutation‐positive children in line with eviQ guidelines — a free resource of evidence‐based, consensus‐driven cancer treatment and genetic testing protocols hosted by Cancer Institute NSW.4 Children at 50% risk of LFS, who have not had genetic testing, receive a six‐monthly clinical review and prompt assessment of any concerning symptoms during the interim period. Over an 18‐month period, the Paediatric Surveillance Clinic has seen 11 children from five families, aged from 3 months to 14 years. Most of these children are at risk of or have a TP53 mutation and one child has a VHL (Von‐Hippel‐Lindau) mutation. The Paediatric Surveillance Clinic offers a holistic service with a multidisciplinary team consisting of a general paediatrician, a paediatric nurse, a paediatric oncologist, a genetic counsellor and a clinical geneticist. The clinic has highlighted the specific and unmet needs of families dealing with HCPS and has allowed for essential integration of genetic, paediatric and oncology services for these families.5 As the number of identified HCPS grows, the Paediatric Surveillance Clinic will continue to offer a flexible service that supports families, assisting with decisions around genetic testing and surveillance for malignancy during childhood and adolescence.

Nicholas Leedman · Murray Princehorn · Nicholas Gottardo · Claire Franklin · Rebecca D'Souza · Catherine E Kiraly‐Borri

Difficulty in achieving proper informed consent for a complex screening test and the varying phenotypic outcomes leaves pregnant women in a precarious situation when results are abnormal The combined first trimester screening test for Down syndrome, involving a nuchal translucency scan and biochemistry at 11–13 weeks, improved detection rates to 90% when compared with the sensitivity of screening by age‐related a priori risk of around 30% for a false positive rate of 5%.1 The advent of non‐invasive prenatal testing (NIPT) in 2010 as a screening test for the common trisomies was revolutionary, with sensitivity, specificity and detection rates unmatched by the combined first trimester screening programs. NIPT was found to achieve a detection rate for Down syndrome of 99.7%, with a false positive rate of 0.04%.2 However, some NIPT providers now additionally offer extended panels and low resolution whole genome sequencing (WGS) including sex chromosome aneuploidies, rare autosomal aneuploidies, and subchromosomal deletions, duplications and recurrent microdeletions. This comes at a cost of a higher false positive rate and lower positive predictive value.3 Moreover, the expanded panels and WGS NIPT raise issues of clinical utility and ethical concerns.4,5 Clinical utility Screening not diagnosis NIPT is based on the detection of cell‐free fetal DNA in the maternal circulation. The placental origin of cell‐free fetal DNA means that NIPT can only be a screening test and is not diagnostic.6 NIPT findings can be confounded by confined placental mosaicism, cell‐free fetal DNA from a demised co‐twin placenta, maternal chromosomal changes or malignancy.6,7 Moreover, a NIPT result will be issued even if the fetus is demised. The current NIPT tests available are for specific chromosomal aneuploidy, extended panels of targeted conditions and low resolution WGS. Targeted and low resolution WGS NIPT Targeted NIPTs (Box 1) interrogate specific chromosomes: standard (usually 13, 18, 21, X and Y) or extended (specific recurrent microdeletions associated with known syndromes, such as 22q11.2 microdeletion [DiGeorge syndrome]).8 Many abnormalities that can be detected by targeted NIPT have varying clinical outcomes (eg, sex chromosome abnormalities and DiGeorge syndrome). Each of these conditions has varying sensitivity, specificity and positive predictive value. Other NIPTs interrogate every chromosome (by low resolution WGS). These tests can potentially screen for aneuploidy of every chromosome (all 22 autosomes and the sex chromosomes), and for subchromosomal gains and losses on every chromosome. There is potential utility in detecting rare or novel large subchromosomal imbalances, as they are likely to be associated with abnormal clinical phenotype when present in the fetus, and may indicate a familial balanced rearrangement. The clinical utility of screening for rare autosomal aneuploidies is less certain. Most rare autosomal aneuploidies (95%) are confined to the placenta, and those which are present in the fetus as well as the placenta often result in early fetal demise.9 The resolution of WGS NIPT is likely to increase as deeper sequencing becomes viable and cost‐effective. Whereas prenatal microarray testing of amniotic fluid in Australia is primarily used in the context of a fetal structural abnormality, higher resolution NIPT could become a general screening test. This would, however, increase both the number of variants of uncertain significance and the likelihood that they are detected in an apparently phenotypically normal fetus.3,10 Ethical concerns Respect for maternal autonomy is an important ethical principle in clinical guidelines for prenatal screening. Recommendation 2 of the Royal Australian and New Zealand College of Obstetricians and Gynaecologists guidelines states: “Screening or diagnostic testing for fetal chromosomal and genetic conditions is voluntary and should only be undertaken as an informed decision by the pregnant woman”.11 In light of the issues surrounding clinical utility and complexity of expanded panels and WGS NIPT, care needs to be taken to ensure that autonomy is respected. Moreover, consent alone cannot be expected to do the ethical heavy lifting, because of (i) the challenges in providing adequate information arising from complexity of the tests; (ii) the risk of power imbalances and “normalisation” of testing; (iii) anxiety resulting from complex and potentially unnecessary medical decisions; (iv) the problem of screening for “normality” and genetic reductionism; and (v) the doctor’s responsibility in determining which NIPT test is clinically indicated. Complexity endangers informed consent Respect for autonomy requires that informed consent is obtained. From a medico‐legal perspective, consent must be given voluntarily. The individual must also be sufficiently informed regarding a test or procedure, including the associated risks and benefits. The requisite extent of information provision is generally determined in accordance with what information a reasonable person, in that person’s circumstances, would expect to receive. From an ethical perspective, however, it is the understanding of information that is important, not merely that a person was given the legally required information. Given the complexity of extended panels and WGS NIPT, ensuring understanding means that significant time needs to be invested. Power imbalances and normalisation Two additional factors could ethically undermine consent for all NIPT options. First, the power imbalance between a doctor and patient, whereby a patient simply agrees because “doctor knows best” and, second, the impression that NIPT is a normal part of care that it would be foolish to reject.12 The anxiety caused by uncertain results It is tempting to respect autonomy by being non‐paternalistic and non‐directive in counselling by giving parents all the information from prenatal testing regardless of its nature. However, this shifts the burden of the uncertain results and the resultant anxiety to the parents. Qualitative and quantitative research shows higher levels of decisional regret among parents whose results identified variation of uncertain significance. At least some parents would not have consented to the test if they had known what this would entail. The lack of certainty by clinicians about what these results might actually mean for a future child increased parental distress.13 The meaning of screening and the danger of genetic reductionism According to the synthesis of screening criteria offered by Andermann and colleagues (Box 2), screening should be used to identify an individual who is high risk for a specific disease or need, thereby filling the perceived gap between standard screening and invasive diagnostics.14 Screening is then followed up with diagnostic tests and appropriate treatment. The availability of extended panels and WGS NIPT (Box 1) increases the tendency away from screening for diseases guided by public health screening principles. It is difficult to identify a recognised need or define the objectives of the screening beyond merely looking to see if there is anything abnormal. Even if these principles were met, one may be detecting placental pathology, or clinical conditions with highly variable outcomes for the fetus. As the resolution of WGS NIPT increases, so does the likelihood of detecting variants of uncertain significance. Provision of extended panels and WGS NIPT should be seen in light of the bigger question of how we see genetic information in our society.15 Research shows that many genetic tests are in effect screening for “normality”, which partly explains the anxiety when variants of uncertain significance are reported.13 This approach potentially changes the purpose of screening from screening for a specific disease to screening for normality by identifying any abnormality in the genome. The error in this thinking is that it assumes that genetic variation is abnormal. Just because a genetic anomaly can be identified does not necessarily mean that it would be phenotypically expressed. Similarly, detection of genes associated with adult onset disease does not necessarily equate to disease, and the possible future development of therapies for currently untreatable conditions cannot be ruled out. Consent is not sufficient to justify a procedure of questionable clinical utility Screening should be recommended or chosen only if there is likely to be a proportionate benefit, and there is no disproportionate burden. What is proportionate rests on a number of objective and subjective factors, but the aforementioned public health screening principles provide a good starting point. We agree with national guidelines that recommend against routine screening for recurrent microdeletions, and recommend provision of in‐depth counselling before screening for sex chromosome abnormalities.11 Recommendations The following recommendations may address the clinical and ethical concerns outlined above. Informed consent is required for all NIPT tests, especially in the context of extended panels and WGS NIPT. Clinicians must understand the different abnormalities targeted by extended NIPT panels and be able to assess and communicate the clinical utility of screening in accordance with a particular patient’s needs, desires and circumstances (Box 1). If ordering WGS NIPT, given that there may be significant uncertainty as to the actual phenotypic or functional manifestation of a genetic variation in a particular child, the consent process should include helping to contextualise limitations and risks in the broader context of the human experience of risk and uncertainty. Genuine shared decision‐making models can empower patient autonomy by helping them to understand the implications of their possible decisions in relation to their values.16 Moreover, decision tools and algorithms that align a variety of scenarios with personal values can facilitate a high quality informed consent process. Higher resolution WGS NIPT should only be used for research purposes until we have robust data regarding its clinical utility. Box 1 – Non‐invasive prenatal testing (NIPT) options: current availability and main advantages and disadvantages CPM = confined placental mosaicism; PPV = positive predictive value; WGS = whole genome sequencing. Box 2 – Synthesis of screening criteria12 The screening program should respond to a recognised need. The objectives of screening should be defined at the outset. There should be a defined target population. There should be scientific evidence of screening program effectiveness. The program should integrate education, testing, clinical services and program management. There should be quality assurance, with mechanisms to minimise potential risks of screening. The program should ensure informed choice, confidentiality and respect for autonomy. The program should promote equity and access to screening for the entire target population. Program evaluation should be planned from the outset. The overall benefits of screening should outweigh the harm.

Joseph Thomas · James Harraway · David Kirchhoffer

Is the current genetics and insurance moratorium an effective long term regulatory solution for Australia? Genetic discrimination in life insurance is a longstanding issue in Australia,1,2 and has been the subject of two government inquiries.3,4 The use of genetic test results in underwriting continues to be self‐regulated by the life insurance industry.5 In 2019, following Parliamentary Joint Committee recommendations,4 the industry voluntarily introduced a moratorium restricting the use of genetic test results in life insurance underwriting for polices worth up to AU$500 000. Although the moratorium is an important step, concerns remain around the financial limits, public awareness, lack of government oversight and compliance monitoring. The impact and effectiveness of the moratorium needs evaluation to inform the planned 2022 review. A new research project has been funded by the Australian Government’s Genomic Health Futures Mission to serve that important function. Genomic testing has the potential to improve disease prevention and public health. For example, predictive testing of BRCA1/2 genes can identify women at high risk of developing breast and ovarian cancer, where risk can be mitigated through preventive surgery and/or screening. As genomic testing becomes more widespread, patients, general practitioners and other health professionals will increasingly be required to address issues related to privacy, data security, genetic discrimination and insurance.2,6 Although health insurance is community‐rated in Australia and therefore not subject to genetic discrimination,1 the use of genetic test results in life insurance is allowed under the Disability Discrimination Act 1992 (Cth). This means that life insurance companies can legally refuse coverage or increase premiums based on genetic test results. A number of ethical, social and medical implications arise when genetic test results are permitted to be used in insurance underwriting, especially predictive testing in otherwise healthy people.1,7 Previous studies show that fear of insurance discrimination deters individuals from taking clinically indicated genetic tests and participating in genetic research.1 In a study where predictive genetic testing for Lynch syndrome (which causes an increased risk of colorectal and other cancers) was offered, the proportion of people who declined testing when informed of the insurance implications was more than double the proportion who declined without knowledge of insurance implications.8 There are different concerns from the insurance industry perspective, including the possible actuarial implications of adding genomic information to risk models. Genomic test results can not only reveal risk (positive results), but also indicate reduced risk (negative results), potentially changing the dynamics of actuarial calculations. The notion of adverse selection, whereby individuals at high genetic risk may be more likely to take out insurance policies, is also raised by insurers. It is critical for the optimisation of genomic medicine that individuals can make informed choices about genetic testing and research participation without fear of insurance implications. Further, moral implications regarding the use of genetic information for insurance underwriting extend beyond actuarial fairness to include consideration of public interests such as justice, beneficence, autonomy and public health.7 Several governments internationally have therefore banned or restricted the use of genetic test results in risk‐rated insurance, including Canada, the United Kingdom and Europe, using various legal mechanisms.9 The National Health Genomics Policy Framework and Implementation Plan 2018–20216 is a strategic policy of the Council of Australian Governments, which recognises the potential of genomics for public health while acknowledging the need for ethical mechanisms for its delivery. Developing a national approach to issues including genetic discrimination was listed as a strategic priority for action in the Framework and listed as the first short term national priority in the implementation plan,6 making it one of the most significant ethical, legal and social issues facing genomic medicine in Australia. However, debate remains regarding the most effective mechanism of regulation. Following previous examination of these issues by the Australian Law Reform Commission and Australian Health Ethics Committee,3 a recent inquiry of the Parliamentary Joint Committee on Corporations and Financial Services into the life insurance industry considered the use of genetic test results in life insurance.4 The report expressed strong concerns about insurer access to genetic information and recommended that: a moratorium be implemented to “prohibit any life insurers from using the outcomes of predictive genetic tests at least in the medium term … as a matter of some urgency and [in] a form similar to the United Kingdom’s Moratorium”;4 the Financial Services Council (FSC), together with the Australian Genetic Non‐Discrimination Working Group (of which the authors are members), assess the consumer impact of a moratorium; and the federal government monitor the implementation of, and adherence to, such a moratorium, and if needed, implement legislation on the issue. The Australian Government has not yet responded to the Parliamentary Joint Committee recommendations. However, the FSC, Australia’s peak national body for life insurers, introduced an industry‐led moratorium in July 2019. Under the moratorium, Australian consumers need no longer disclose their genetic test results when applying for policies up to $500 000 for death/total permanent disability, $200 000 for trauma/critical illness, and $4000/month for income protection cover.10 The moratorium applies to all genetic test results, including research results and results obtained from internet‐based direct‐to‐consumer tests, which are increasingly resulting in clinical referrals.11 Above these financial limits (which are cumulative across multiple policies), life insurers can still ask for, and use, any existing genetic test result, which can lead to refused or delayed cover, exclusions or increased premiums. However, insurers must not require applicants to undergo a genetic test. Applicants can choose to disclose a favourable genetic test result (showing that an individual with a family history of a genetic condition does not have the familial genetic variant) to offset the effects on underwriting of an adverse family history. The FSC moratorium is a self‐regulated industry standard which is not legally enforceable — insurance companies’ legal right to discriminate on the basis of genetic test results remains. By contrast, the UK moratorium (which commenced in 2001) is an agreement between the UK government and the Association of British Insurers. It applies to all life insurance policies without any financial limits, with only one exception for Huntington disease, a progressive, neurodegenerative genetic disorder. Predictive genetic test results for Huntington disease must be disclosed by individuals in the UK only when applying for cover worth over £500 000 (about AU$900 000).12 All other individuals can make informed decisions about whether to have genetic testing or participate in genomic research without concerns about insurance implications. The FSC moratorium is an important step towards consumer protection, but concerns remain around its financial limits, interpretation of its terms, and lack of compliance monitoring. The FSC moratorium has no government or independent regulatory oversight, and as recommended by the Parliamentary Joint Committee, there is a critical need to monitor its implementation and effectiveness. The FSC will review the moratorium and its terms in 2022, to consider amendment and/or extension beyond its current 2024 end date.10 Currently, there are no mechanisms in place to collect independent evidence from different stakeholder perspectives to inform this review and the Australian Government has not indicated any intention to do so directly. A new research project, funded by the first competitive round of the Genomic Health Futures Mission, part of the Australian Government’s Medical Research Future Fund,13 has now commenced to serve that critical function until 2023. The A‐GLIMMER (Australian Genetics and Life Insurance Moratorium: Monitoring the Effectiveness and Response) project brings together leading researchers, clinicians, patient groups, and policy experts in Australia to answer the question of whether the FSC moratorium is an adequate and effective long term regulatory solution for Australia. The project aims to address this question by collecting a range of quantitative and qualitative data after the implementation of the moratorium, from different stakeholders including consumers, health care professionals, researchers and the insurance industry. In some cases, the data collected will be directly comparable to similar data collected and published before the moratorium.14,15 The project has widespread support across the community. More than 20 project partners, including the FSC, and other supporting bodies have provided written support and pledged resources towards the study. The project is endorsed by the Victorian Department of Health and Human Services, the Human Genetics Society of Australasia and Australian Genomics, a collaborative national network of clinical, research, academic and community organisations dedicated to implementation of genomics for health and the development of appropriate genomics policy. The overarching aim of A-GLIMMER is to ensure sufficient evidence is collected in the coming years to inform government and the 2022 FSC review, to help determine the effectiveness of the FSC moratorium as a long term regulatory solution in Australia. See the Box for a summary of project aims. A‐GLIMMER is divided into four work streams, which will collect data from consumers, health professionals, research studies and the insurance industry. A final report will be compiled at the conclusion of the project, and will be provided to the federal government to assist with future policy decisions. Although the project will not conclude until 2023, its findings will help inform the proposed FSC review in 2022. Achieving an adequate policy solution to this issue in Australia is essential for ensuring optimal integration of genomics into Australian health care, engendering public trust and consumer participation in genomics, and paving the way to realise the many benefits of genomic medicine for Australia. Box – Aims of A‐GLIMMER (Australian Genetics and Life Insurance Moratorium: Monitoring the Effectiveness and Response) A‐GLIMMER will: assess dissemination and awareness of the Financial Services Council moratorium following its implementation describe the impact of the moratorium on consumers, health care, research and financial services evaluate the effectiveness of the self‐regulated Financial Services Council moratorium as a long term regulatory solution

Jane Tiller · Ingrid Winship · Margaret FA Otlowski · Paul A Lacaze

Hospitals in the Northern Territory often operate beyond capacity and serve a sparsely distributed population with rates of chronic disease and household overcrowding that are higher than in many other parts of Australia. The NT consequently adopted particularly strict public health measures to avert the potentially catastrophic consequences of community transmission of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), including supervised isolation until viral clearance of all people with confirmed SARS‐CoV‐2 infections (Supporting Information 1). This measure provided a unique opportunity to study the duration and trajectory of viral shedding in relation to clinical illness. In this article, we describe epidemiologic, clinical, and virological aspects of the first 28 cases of coronavirus disease 2019 (COVID‐19) in the NT. The Top End and Central Australian Human Research Ethics Committees approved the study (reference, 2020‐3737). Between 4 March and 4 April 2020, 28 cases of COVID‐19 were diagnosed in the NT, all linked to overseas or interstate travel. The median age of patients was 45.0 years (range, 1.5–75 years); 16 were women (Supporting Information 1, table). Two patients required supplemental oxygen, one of whom also required intubation. There were no deaths. Symptoms had been present for a median 3 days (range, 0–16 days) before oro‐nasopharyngeal swab collection and lasted a median 9.5 days (range, 4–18 days). Viral RNA could be detected by multiplex tandem real‐time polymerase chain reaction (PCR) assay (AusDiagnostics; Supporting Information 1) for a median 25 days after symptom onset (range, 14–41 days; interquartile range [IQR], 21–32 days), and in most patients for more than two weeks after symptom resolution (median, 17.5 days; range, 2–31 days; IQR, 14.5–22.5 days) (Box 1). Within‐patient variability in viral target cycle threshold values during follow‐up was considerable (Box 2; Supporting Information 1, figure), despite adequate and consistent amounts of human biologic material in test samples (data not shown). Prolonged compulsory isolation was distressing for several patients. The phylogeny of the 27 available NT viral genomes was consistent with acquisition in locations on all inhabited continents (Box 3). Five genetic clusters were evident (maximum of one single nucleotide polymorphism within each cluster) that were also epidemiologically linked by shared travel or household contact. The SARS‐CoV‐2 genomes from two independent travellers without epidemiologic connections were identical, but matched other publicly available genomes, highlighting the importance of interpreting genomic analyses in their epidemiologic context. The priority of the strict NT isolation requirements for patients with COVID‐19 was viral containment at a time when data on the duration of viral transmissibility were sparse. More recent evidence suggests that viable SARS‐CoV‐2 is rarely isolated more than 10 days after symptom onset,1,2,3 and requirements have consequently been eased, while maintaining supervised isolation with health management during the period of greatest infectivity. The high degree of temporal variability in viral shedding during follow‐up indicates that a single assay is not adequate for excluding infection in patients at epidemiologic risk of COVID‐19. The NT implemented particularly aggressive public health measures to contain SARS‐CoV‐2 transmission. Epidemiologic and genomic analyses suggest that this response has successfully prevented local community transmission of the virus. Box 1 – Time course of 28 cases of coronavirus disease 2019 (COVID‐19) diagnosed in the Northern Territory, 4 March – 4 April 2020 Each line represents a single patient. Day zero is the day of collection of the first SARS‐CoV‐2‐positive specimen; thickened sections indicate the period of COVID‐19 symptoms. Closed circles indicate positive SARS‐CoV‐2 assay results, hollow circles negative assay results. Patients 13 and 15 (lighter marking) required supplemental oxygen. The bottom line summarises the median duration of symptoms prior to diagnosis, the median duration of symptoms, and the median time to viral clearance. Box 2 – Multiplex tandem polymerase chain reaction cycle threshold values for detection of the SARS‐CoV‐2 open reading frame 1a gene (ORF1a) Box 3 – Maximum likelihood phylogenetic tree, depicting SARS‐CoV‐2 genomes from the Northern Territory and elsewhere SARS‐CoV‐2 = severe acute respiratory syndrome coronavirus 2. The phylogenetic tree shows that SARS‐CoV‐2 genomes in the Northern Territory (on the inner side of the outer ring) were drawn from across the range of genomes reported elsewhere (outer ring). NT travel‐related cases with epidemiologic links formed genomic clusters. Two cases without epidemiologic links also comprised a cluster, but the genomes were identical with overseas genomes. The context genomes were obtained from GISAID (https://www.gisaid.org), with region based on location of the submitting laboratory; the Wuhan‐Hu‐1 genome was used as an outgroup, and the scale bar indicates substitutions per site.

for the Northern Territory COVID‐19 Response Group

Should medically significant genetic results be offered to research participants or their at‐risk relatives? Australian research studies now generate genetic information on thousands of participants. Some genetic results, present in a small portion of participants (< 5%), are considered medically actionable, meaning they are associated with increased risk of adult‐onset diseases, where effective risk management, prevention or treatment exists (eg, inherited cancer or cardiac disorders).1 The National Statement on Ethical Conduct in Human Research,2 which considers genomic research at Chapter 3.3, now requires an ethically defensible plan for return (or non‐return) of genetic research results. Box 1 summarises the guidelines that are relevant to the return of genetic results to research participants.2 Returning genetic research results can be life‐saving, alerting participants to preventive steps that they would not otherwise have taken. Most participants identified in research studies have no clinical features or family history of the indicated disease, are unaware of their genetic risk, and would not qualify for publicly funded clinical criteria‐based genetic testing. Among the international genomics community, there is growing consensus that medically actionable genetic research results should be made available to participants.3 The American College of Medical Genetics and Genomics published a list of genes related to medically actionable conditions, in which results should be returned if identified during clinical testing.1 This gene list has been used to guide the return of research results in some United States studies,4 but has not been adopted by the National Health and Medical Research Council or other Australian bodies. However, the National Statement makes it clear at 3.3.41 that “researchers have an obligation to have a process in place for the return of findings that are of proven validity and of health significance to the participant, or relative, subject to participant consent”.2 However, even where participant consent has been obtained, not all Australian studies are returning medically actionable results, due to varying ethical and practical challenges. For example, research participants may provide samples for altruistic reasons, before research analysis, without expectation of re‐contact. Should results be returned to these individuals, especially those unaffected by indicated disease? Is there a legal or ethical requirement to make results available or liability for withholding them? The National Statement provides some guidance (Chapter 3.3) regarding which results should be returned,2 but ultimately researchers determine whether to return results. As the National Statement indicates, return of results should be limited to those genes with validity and utility (3.3.29 and 3.3.41).2 However, pathogenic variants in medically actionable genes are not fully penetrant, meaning that not all at‐risk variant carriers develop the disease.5 Risk estimates for many genes are still uncertain, complicating decisions around medical actionability and the time frame for returning results. Some participants may experience surprise or distress on learning about genetic risks. Returning results may also raise the possibility of out‐of‐pocket medical costs or increased insurance liabilities for younger participants. Genetic results should be delivered by a medical professional, with genetic counselling and clinical support provided, as noted by the National Statement (3.3.31 and 3.3.32).2 This requires time and resources, which are often limited. Thus, despite clear guidance in the National Statement, some research studies do not return results even where results are clinically valid and of undisputed relevance to participants’ and family members’ health, and the participant has consented to receive such results. To assist with these challenges, a national service to support the return of genetic results from research studies has recently been developed6 and is now operational. Research cohort case studies Here, we present two case studies from Australian epidemiological research (Box 2). Lifepool,7 a large community‐based study of women in the general population, and ASPREE (ASPirin in Reducing Events in the Elderly),8 a large cohort study of healthy older people, have both commenced genetic analysis and have been faced with decisions regarding the return of genetic results. These case studies highlight the challenges and opportunities related to this complex issue. ASPREE's older population particularly raises unique challenges.9 Lifepool has shown that return of genetic results prompts preventive interventions for women with variants in high risk breast cancer genes, most of whom would not have been identified through current clinical criteria‐based testing.7 To date, Lifepool has contacted 73 women previously unaware of their high risk variants. None of the women identified with a cancer‐causing variant would have been eligible for publicly funded testing through the Australian clinical system. Most women took proactive steps to mitigate risk after receiving genetic results. Of the 73 women, 23 so far have undergone risk‐reducing surgery (bilateral oophorectomy), mitigating their cancer risk.11 This could be life‐saving, given the high lifetime risk and low survival rates for ovarian cancer associated with high risk variants. The shared nature of DNA means genetic results are also relevant to participants’ blood relatives. Beyond participants who directly received results, 63 relatives were also tested through cascade testing, 32 of whom were also found to have a high risk variant. These relatives were, on average, substantially younger than the original participants (Box 3), making this information even more valuable for prevention. ASPREE biobank participants consented to re‐contact regarding genetic results relevant to personal or family health. In accordance with the National Statement (3.3.36 and 3.3.37),2 an ethically defensible plan outlining the return of genetic results was approved by the Alfred Hospital Human Research Ethics Committee in 2015.9 However, there is ongoing debate about the most appropriate strategy, given the age of the cohort (average, 75 years) and primary purpose of the study — an aspirin prevention trial (as opposed to genetic research study). ASPREE has returned other types of (non‐genetic) medically actionable research results, including abnormal magnetic resonance imaging, blood pathology and cognitive assessments. However, genetic results have been treated differently, with unique challenges. Many older ASPREE participants who carry medically actionable variants have seemingly outlived their increased risk, displaying no signs of indicated disease at 75 years of age and older.12 Is the information still medically actionable? Do participants still want to know? Should results be returned for the benefit of younger, potentially high risk family members? What about ASPREE participants who are in cognitive decline or deceased? Is ASPREE obliged to contact these individuals, or their relatives, to provide genetic results? Despite having detected genetic information through research analysis that is clinically valid and of clear relevance to personal or family members’ health, ASPREE has not yet commenced returning genetic results, seeking to achieve an appropriate harm–benefit balance.9 The applicable Human Research Ethics Committee recently discussed a possible strategy of offering results via an opt‐in model, where participants register interest following a newsletter notification. Although well intended, this approach is problematic. First, only a fraction of participants would receive or read the newsletter article, limiting the number who would be informed. Second, only about 1% of the cohort will have a medically actionable variant, meaning the likelihood that those participants will have opted‐in is very small. Finally, ASPREE participants have already consented to re‐contact on the basis of medically actionable genetic results, so re‐consent is not required. The proposed opt‐in model compromises equity in ensuring high risk participants are contacted and offered results ethically. The consequences of a passive approach to returning results are notable. For example, two male ASPREE participants were found through the study analysis to have high risk breast cancer variants. Neither participant had any relevant personal cancer history. Analysis of collected family history data showed that both had daughters (who have a 50% chance of having the same pathogenic variant) who developed breast cancer under the age of 50 during the ASPREE trial. These women did not have a family history of breast cancer required to prompt clinical genetic testing through clinical services. Yet their fathers’ results, if known, may have prompted genetic testing or high risk breast cancer screening for the daughters. This information was clinically significant and relevant to family health, despite its questionable health benefit to the male participants. Although the time for prevention has passed for those participants’ daughters, ASPREE must now consider the return of results to other participants with medically actionable results. Currently, there is no Australian legal requirement to inform research participants of medically actionable genetic results — any imperative to offer results is ethical. Whether any ethical imperative extends to preventing disease in participants’ relatives is unclear,13 although it is contemplated by the National Statement (3.3.32 and 3.3.41).2 A concern arising when considering return of results in ASPREE is that elderly research participants may not want to know about genetic results. However, other studies suggest that most research participants do want to receive genetic information, even if only for their family members’ benefit.14,15 A recent international survey on preferences for genetic results14 showed no significant difference between elderly and younger groups. Evidence suggests that older participants may be more interested in genetic results, especially if family members may benefit.14 Another challenge arises where participants with medically actionable genetic results are deceased or in cognitive decline. In these circumstances, the benefit of returning results to next‐of‐kin is for relatives. Several Australian research studies return genetic results purely for family members’ benefit, demonstrating the acceptability of this approach. The Australian Ovarian Cancer Study commenced returning genetic results of deceased women to next‐of‐kin more than ten years ago.16 Recently, the TRACEBACK study archived DNA samples of women who died from ovarian cancer, to identify genetic risk variants and notify at‐risk relatives.17 These programs conduct genetic testing on DNA of deceased people who cannot derive personal benefit, for the benefit of at‐risk relatives. Conclusion There is a growing consensus on the ethical imperative to offer research participants medically actionable genetic results. Studies show high acceptability for receiving genetic results, and the preventive health benefits are clear. Although the National Statement provides guidance, questions remain regarding the legal obligations and disclosure methods, particularly when research participants lack the capacity to make decisions about receiving genetic information. As genetic information becomes more pervasive and valuable to preventive medicine, the return of medically actionable genetic results will become increasingly important from ethical, legal and medical perspectives. Box 1 – National Statement on Ethical Conduct in Human Research: guidelines relevant to return of genetic results2 Guideline Content 3.3.26 In considering whether to return results of research, researchers should distinguish between individual research results and overall research results. Researchers should consider how these results will be provided to participants, how the process of returning results will be managed, and the risks of the return of individual research results and overall research results. 3.3.27 Return of findings and results relating to an individual participant depends on the contextual relevance of the findings; some genomic research findings must be returned, some findings may be returned, and some findings should not be returned. 3.3.29 Once there is sufficient evidence and agreement that a finding or result is clinically significant, participants should be advised that research results or findings that may be returned will first need to be confirmed according to applicable guidelines; eg, at a National Association of Testing Authorities accredited laboratory. 3.3.31 Any plan to return individual research results should include linkage with a clinical service and access to genetic counselling. The plan should specify any expertise to which the project team might require access. 3.3.32 The return of results or findings of significance for the health of the participant or relative is the responsibility of the appropriate clinical service or, where such a service is not available, the participant's clinician in consultation with the research team. 3.3.36 Researchers must prepare and follow an ethically defensible plan to manage the disclosure or non‐disclosure of genomic information of potential importance for the health of research participants or their relatives. 3.3.37 The ethically defensible plan must be approved by a Human Research Ethics Committee. Step 1: Determination of whether findings will be returned Genomic research falls into three categories: research with findings that must be returned; research with findings that may be returned; and research with findings that should not be returned. The relevant factors to be considered to determine whether findings must, may or should not be returned include: analytic (scientific) and clinical validity; significance to the health of the participants/relatives; and clinical utility. 3.3.41 Where there will be any return of findings to participants, they should be advised as to which findings will be returned and which will not be returned, as follows: that researchers have an obligation to have a process in place for the return of findings that are of proven validity and of health significance to the participant or relative, subject to participant consent; that if researchers plan to return findings during the project that are of proven validity but are not of health significance to the participant or relative, they will need to justify this plan; that there is no obligation on researchers to look at or assess findings outside of the scope of the research; and that there is no ongoing responsibility on researchers to review findings of a research project after the project has been completed in order to discover or assess findings that may have become returnable due to later scientific advances. Box 2 – Research cohort case studies Lifepool study7 ASPREE study8 Australian study aiming to improve women's health, particularly with respect to breast cancer Randomised, placebo‐controlled Australian trial for daily low‐dose aspirin, and ongoing observational cohort study of ageing Participants 50 000 women 19 000 healthy older men and women aged > 70 years Consent for genetic testing and return of results DNA samples were contributed to a “pool” of data and consent given for unspecified future research Participants were informed they would be contacted if information relevant to their health was found DNA samples were contributed to a biobank with consent for future genetic research Participants were informed they may be contacted if information relevant to their health was found An ethically defensible plan for re‐contacting participants with medically actionable results was approved by the applicable HREC9 Genetic testing conducted 14 799 samples were tested for changes in high risk breast cancer genes, which confer significantly increased risk of breast and ovarian cancer Risk can be mitigated through breast screening10 and/or preventive surgery11 13 131 samples were tested for changes in medically actionable genes, including high risk cancer genes Personal and family (first degree relatives) history of cancer was collected throughout the study Genetic results of relevance Following notification of women with high risk results: 97% made an appointment with a familial cancer centre to discuss results further 97% proceeded with confirmatory genetic testing 60% have undergone risk reducing oophorectomy An average of 3.3 relatives were tested per index case 51% of relatives tested also had the genetic variant 53 participants had a medically actionable result in high risk cancer genes12 No genetic results have been returned as yet At an estimated minimum of 3.3 cascade cases per index case,7 offering the return of results to 53 participants could reach a minimum of 175 Australians at high risk of developing familial cancer ASPREE = ASPirin in Reducing Events in the Elderly. Box 3 – Distribution of age among family members accepting cascade testing through a familial cancer centre (FCC) compared with index cases identified through Lifepool6 Although index cases identified through Lifepool often approach the age at which genetic risk is less relevant, a large proportion of the family members identified are considerably younger, at an age where preventive benefits can be maximised.

Jane Tiller · Alison H Trainer · Ian Campbell · Paul A Lacaze

Publicly funded reproductive carrier screening programs must weigh up a number of ethical considerations Reproductive genetic carrier screening (RCS) is undertaken by individuals or couples to determine their likelihood of having a child with particular autosomal recessive or X‐linked genetic conditions. It can be undertaken by anyone of reproductive age who wishes to have it, regardless of their family history or ancestry, and either before or during pregnancy.1 Some forms of RCS are currently available in Australia on a user‐pays basis, costing around $400–$500 per person. It is usually accessed via general practitioners but can also be accessed directly from testing companies.2 People who receive an increased chance result are offered genetic counselling to explore their reproductive options, which might include steps to avoid having a child with a genetic condition. Taking the test before pregnancy gives those with an increased chance result a wider range of reproductive options compared with prenatal testing.3 The Australian Reproductive Genetic Carrier Screening Project (Mackenzie's Mission), announced by federal Health Minister Greg Hunt in 2018, is a research project offering RCS to 10 000 Australian couples. Recruitment via participating health professionals commenced in late 2019. Mackenzie's Mission is gathering evidence — including clinical, laboratory, psychosocial, health economic and ethical aspects — to inform how publicly funded screening could be operationalised in Australia within ten years.4 Here, we reflect on the ethical implications of RCS in Australian health care.5 While the issues raised apply to all types of RCS, we focus on aspects relating to large scale, publicly funded initiatives like Mackenzie's Mission. Ethics and the goals of RCS A central ethical issue for large scale RCS initiatives is how their goals are described. Two main foci for articulating the goals of such programs are (i) outcomes for individuals and their families, such as reproductive autonomy; and (ii) outcomes for populations, such as reduced incidence of certain genetic conditions. It has been argued that a goal of seeking to reduce the population incidence of babies who will develop severe genetic conditions is inappropriate for RCS.6 This line of reasoning draws partly on concerns about perceived coercion; when RCS is offered routinely, couples may perceive that participating is the right thing to do, even if testing is optional.7 Additionally, such a goal might be interpreted as implying that couples who receive an increased chance result are then obliged to take action to avoid the birth of an affected child. Any future national program must be delivered as a genuinely optional intervention, respecting couples’ values and preferences. It has also been argued that the goal of reducing the incidence of certain genetic conditions in the population expresses an unfavourable judgement about the value of the lives of people who currently live with such a condition.8 Therefore, in the case of RCS it is considered more ethically acceptable for a program's stated aim to be aligned with the first set of outcomes mentioned above; namely, to support couples’ reproductive autonomy through provision of relevant information to enable choices that are consistent with their values.1 RCS programs are also motivated, at least in part, by the desire to mitigate harms that couples who have parented a baby or child with a severe or fatal genetic condition experience. These harms include the grief of losing a child or witnessing one's child suffering. RCS might enable some parents to avoid such distressing experiences. Emphasising the severity of a condition included in a screening program arguably lessens any implied negative judgement about people living with genetic conditions screened for. However, ethical debate on what constitutes a severe or serious condition remains ongoing.9 Ethical aspects of gene selection A significant component of designing a publicly funded RCS program is determining which genes warrant inclusion for testing.10 Since screening can be stigmatising for people living with the genetic conditions screened for, it is considered most ethically defensible to screen only for genes associated with severe childhood‐onset conditions.1,3 However, because perceptions surrounding seriousness and severity are not purely objective,9 any RCS program must carefully weigh the diverse ways in which a condition can present, as well as the implications of that condition for the person and their family. There are also ethical aspects regarding the classification of gene variants identified during the testing process.11 There can be a degree of uncertainty as to how strongly a particular variant is associated with a genetic condition, an issue compounded in population screening because there is no index case (proband) to facilitate interpretation. This has ethical implications because reporting a variant as disease‐causing when it is not may mean a couple will experience additional uncertainty and perhaps go through unnecessary tests or interventions. On the other hand, not reporting a variant that does turn out to be disease‐causing means a couple may go on to have a child with a serious condition despite receiving a low chance result from RCS. This issue will remain important for some time, especially as variant databases are still developing. Consent for RCS: enabling meaningful choices Whether and how to gain consent can be contentious in many public health screening programs.12 While both consent and pre‐test education are important for RCS,1 determining how best to do this can be complex. It has been argued that when screening is perceived as routine, people will be less likely to reflect critically on whether it is appropriate for them, or to consider whether the results will be relevant to their decision making.7 Support for pre‐test decision making such as educational videos and decision aids can help couples consider the implications of an increased chance result and their options for reproduction. Mackenzie's Mission is one of several large scale population‐based RCS initiatives globally that have curated large panels of genes to test using a couple‐based model.5,10,13 It is important for participants to understand that RCS is designed to provide the couple with information that might help with decisions about reproduction, rather than to convey genetic risk information for their own health. Participants will also be encouraged and supported to reflect on their values and their goals for testing, to help them decide whether this screening will be useful or important for them.14 Reporting results: ethical implications Results of any genetic test can be complex and might be uncertain.15 As such, results from RCS need to be provided in a way that is meaningful and useful. To optimise the utility of their results, participants will require a basic understanding of key concepts such as what it means to carry a recessive genetic condition, and the implications of an increased chance finding. It is also important to ensure that participating in screening is not interpreted as guaranteeing that someone will have a healthy child. Publicly funded population RCS globally is tending towards reporting couple‐based findings. Evidence suggests that participants understand and accept this approach and that it is feasible as a population screening model.5,13,16 Mackenzie's Mission participants will be informed when they both carry the same disease‐causing variant for an autosomal recessive condition, or when the genetic mother is found to carry one of the X‐linked conditions screened for. Reporting only couple‐based findings is justifiable from an implementation perspective, for both programmatic and pragmatic reasons. Programmatically, RCS aims to inform reproductive choices, so it provides couples with information relevant to those choices. Any potential for false reassurance can be carefully addressed during the pre‐ and post‐test education processes. Pragmatically, publicly funded RCS would be prohibitively expensive to offer if it reported individual carrier results, as the majority of individuals screened are likely to be a carrier for something.16 Each of these people would then need individual follow‐up, despite their future offspring having a very low chance of actually having that autosomal recessive condition, even if they were to re‐partner.17 Moreover, this information has no clinical utility for the individual's own health. It also has the potential to provoke anxiety. As such, it is premature and potentially inequitable to provide individuals with information relating to their individual carrier status without providing further support. Further research will inform considerations of the ethical and psychosocial aspects of using an RCS framework to report individual results, including the possibility of offering individual results for a limited number of the more prevalent conditions on the panel. Public funding How RCS is funded is also ethically relevant, not least due to the perceived endorsement of screening by the state when a program is publicly funded. A formal, publicly funded, screening program may have advantages,18 but public funding might also carry tacit value implications. Experience with antenatal screening suggests that blame and guilt can be associated with declining an offer of screening.19 Funding models can also reinforce routinisation, where a screening offer might be perceived as encouraging or even coercing couples to terminate a pregnancy if a genetic condition is identified in the fetus.7 Within public funding structures, ethical issues also arise from the mode of offer of RCS, either in the context of a formal population screening program (likely to be delivered by centralised, publicly funded entities) or via a Medicare item number. Provision via Medicare will allow any provider who can meet the item number requirements to offer the test, and as such is likely to attract a greater commercial presence in RCS. The resulting fragmentation might constitute a lost opportunity for uniform evaluation of program effectiveness and might also give rise to inconsistencies in aspects of test provision, such as counselling. On the other hand, provision through Medicare may also enable RCS to be rolled out more quickly than establishing a formal population screening program. Cost‐effectiveness of population‐wide RCS has not yet been established conclusively by the existing evidence;11 however, one of the aims of Mackenzie's Mission is to generate such evidence for the Australian health care system. RCS and community values Underlying these ethical considerations is the question of how RCS reflects societal values. While most people are likely to agree on core principles such as respecting couples’ choices about whether to participate in screening, there will also be variations in preferences between communities, families and individuals.20 Future delivery of a national RCS program in Australia will need to recognise and respond to this diversity, while also upholding the values that motivate the program. The central values for RCS in Australia are good health outcomes for families and communities, alongside respect for all Australians, equity in program design and delivery, and reproductive autonomy.

Lisa Dive · Ainsley J Newson

Clinical record A 70‐year‐old man with multiple myeloma was admitted to our hospital in 2018, having been hospitalised 10 months previously in the United Kingdom. Following admission to our facility, routine collection of clinical specimens was performed in the setting of an episode of febrile neutropenia. Candida auris was isolated in a urine specimen collected in the presence of an indwelling urinary catheter, without accompanying pyuria. Screening of ward contacts (n = 73) was subsequently performed by collection of composite axilla and groin skin swabs, together with swabbing of possible clinical sites of infection (eg, wounds, catheter sites). Swabs were plated onto Candida chromogenic agar and incubated aerobically for 48 hours at 35°C. Any colonies not typical for C. albicans or C. tropicalis were identified using matrix‐assisted laser desorption ionisation time‐of‐flight (MALDI‐TOF) mass spectrometry. The routine regimen of daily cleaning and disinfection of rooms with 1000 ppm sodium hypochlorite solution was continued. Enhanced infection control measures, including contact precautions and single‐room isolation were instituted. A multidisciplinary taskforce coordinated screening, laboratory and prevention strategies. Review of laboratory reports for the preceding 12 months confirmed this to be the first documented C. auris isolate at our facility. One ward contact, a 38‐year‐old man with diffuse large B cell lymphoma, was identified as colonised with C. auris. The organism was detected in a urine specimen collected in the presence of a long term indwelling urinary catheter. This patient had been admitted to a health care facility in the United Arab Emirates, before direct transfer to our facility about 3 months earlier. Colonised patients had been located in a common ward for 19 days, each in a single room with dedicated bathroom and patient care equipment. They had also been managed on an outlying ward for brief periods (3 and 2 days, respectively) separated in time by 2 days. Neither patient developed clinical features of urinary tract or disseminated C. auris infection and antifungal therapy was not administered. Isolates were confirmed as C. auris by MALDI‐TOF mass spectrometry (each with score of 1.75). Antifungal susceptibility testing by broth microdilution demonstrated isolates were resistant to fluconazole (minimum inhibitory concentration [MIC] > 256 mg/L) and susceptible to caspofungin (MIC, 0.25 mg/L) and anidulafungin (MIC, 0.12 mg/L for Patient 1 and 0.25 mg/L for Patient 2). To investigate relatedness of isolates, whole genome sequencing and bioinformatics analysis were performed. Phylogeographic analysis demonstrated that both were related globally to those contained in the India–Pakistan clade. The median pairwise single nucleotide polymorphism distance between the two isolates was 167, suggesting that while these isolates were related, it was not possible to confirm whether transmission had occurred. Discussion Candida auris is an emerging, drug‐resistant yeast, responsible for hospital outbreaks internationally.1 First recognised as a new species of Candida in 2009, cases have been reported in over 30 countries, including the United Kingdom and United Arab Emirates.1,2 In outbreak settings, bloodstream, urinary tract and deep tissue infections have been reported, in addition to colonisation. The majority of isolates are fluconazole resistant,3 with variable resistance to amphotericin B and the echinocandin class of antifungal agents. Infection is associated with a crude mortality of 30%.3 Key differences between C. albicans (the most frequently identified Candida species in Australia) and C. auris are summarised in the Box. Risks for C. auris acquisition include admission to a high dependency unit, presence of invasive medical devices, underlying immunocompromise or chronic disease and receipt of antibiotic or antifungal agents.4 One case of C. auris invasive disease has previously been reported in Australia,5 but to our knowledge the two cases identified at our facility represent the first possible transmission of C. auris in Australia. Identification of C. auris is challenging, with potential misidentification by routine biochemical methods. If C. auris is included in the reference profile database, MALDI‐TOF mass spectrometry may be used to confirm diagnosis. DNA sequencing also provides confirmation, together with data regarding origins and potential transmission in health care settings.3 Collection of bilateral axilla and groin skin swabs as a combined screening specimen is recommended for optimal yield.6 European and United States guidelines recommend screening of all room contacts of patients with C. auris.6,7 Screening of additional patients (eg, whole ward) is necessary where more than one case is identified. Targeted surveillance of patients who have recently had at least one overnight stay in an overseas facility is also recommended, especially if from a country reporting C. auris cases.6,7 Our experience highlights the importance of this strategy. Clinicians should be aware of risks for C. auris acquisition, including overseas health care encounters. In high risk settings, and where a case of C. auris infection has been identified, timely screening of patients is required to ensure that appropriate control measures are instituted. Lessons from practice Candida auris is an emerging drug‐resistant yeast, now reported in Australian health care facilities. In contrast to C. albicans, which is commonly isolated in community and health care settings, C. auris is generally only identified in high risk hospitalised populations. Risks for acquisition include intensive care or high dependency unit admission, presence of invasive medical devices, underlying immunocompromise or chronic disease, and receipt of broad spectrum antibiotics or antifungal agents. Strict infection control measures, including contact precautions and isolation, are required to reduce risks of transmission. Screening for colonisation is an important element of infection control strategies, and a composite skin swab of axilla and groin is recommended. Timely detection requires laboratory identification. MALDI‐TOF mass spectrometry may be used for confirmation, and whole genome sequencing may provide additional information on possible transmission events. Health care facilities must ensure processes are implemented for screening of patients who have received health care in overseas hospitals. Box – Comparison of clinical and epidemiological characteristics of Candida albicans and Candida auris Candida albicans Candida auris Colonisation Colonisation of patients in community and health care settings is common; a commensal of skin and gut of immunocompetent and immunocompromised hosts Colonisation of patients associated only with hospital outbreaks or transmission, also identified in environment and equipment in hospital outbreak settings Infection Infection most frequently at mucosal sites (eg, oropharyngeal, vulvovaginal); bloodstream and urinary tract infections less frequent Bloodstream, urinary tract and wound infections reported Risks for infection ICU or HDU admission, invasive medical devices, major abdominal surgery, solid tumours, haematological malignancies, broad spectrum antibiotics ICU or HDU admission, invasive medical devices, underlying immunocompromise or chronic disease (eg, diabetes, chronic lung disease, renal failure, cardiovascular disease, or malignancy), broad spectrum antibiotics or antifungal agents Geographical distribution Ubiquitous, community and health care settings Reported only in health care settings, expanding global distribution Laboratory identification Culture using selective chromogenic media Culture together with MALDI‐TOF or DNA sequencing Antifungal resistance Generally susceptible to fluconazole Resistance to fluconazole is likely* HDU = high dependency unit; ICU = intensive care unit; MALDI‐TOF = matrix‐assisted laser desorption ionisation time‐of‐flight mass spectrometry. *Note: agreed fluconazole minimum inhibitory concentration breakpoints for C. auris have not been established

Leon J Worth · Simon J Harrison · Michael Dickinson · Annaliese Diemen · Jennifer Breen · Susan Harper · Caroline Marshall · Deborah A Williamson · Karin A Thursky · Monica A Slavin

Genetic research with Indigenous Australians is achievable with community engagement and appropriate governance mechanisms in place

Steven YC Tong · Heather D'Antoine · Melita McKinnon · Kyle Turner · Maui Hudson · Ngiare Brown · Jonathan R Carapetis · Dawn C Bessarab

Australian Genomics is calling for a change in research ethics and governance frameworks

on behalf of Australian Genomics

Universal tumour testing strategies for guiding germline genetic testing are likely to be cost-effective compared with no testing

Yoon‐Jung Kang · James Killen · Michael Caruana · Kate Simms · Natalie Taylor · Ian M Frayling · Tristan Snowsill · Nicola Huxley · Veerle MH Coupe · Suzanne Hughes · Victoria Freeman · Alex Boussioutas · Alison H Trainer · Robyn L Ward · Gillian Mitchell · Finlay A Macrae · Karen Canfell

To the Editor: The authors of a recent Guttmacher–Lancet Commission article1 point out that Australia is a signatory to the United Nations Sustainable Development Goals, which nominate sexual and reproductive health as rights. The key focus of the article on the Guttmacher–Lancet Commission is around human immunodeficiency virus and sexually transmitted infections, unintended pregnancy, contraception, abortion, and sexual violence.1 These are all important reproductive health rights to address. While the Guttmacher–Lancet Commission also includes maternal and newborn health, there is no mention of reproductive carrier screening. Reproductive carrier screening involves testing prospective parents — before pregnancy, ideally, or in the early stage of pregnancy — for carrier status for autosomal recessive and X‐linked recessive disorders, and giving reproductive choices to people at increased risk of having an affected child. These choices include pre‐implantation genetic diagnosis, prenatal diagnosis by chorionic villus sampling or amniocentesis, donor gametes or embryos, adoption, having no children, or ignoring the risks. Most couples with or at risk of having an affected child have no family history, which is typical for recessively inherited diseases. Reproductive carrier screening is available in Australia, although only through a fee‐for‐service mechanism, but most couples are unaware of its availability. Currently, screening for cystic fibrosis, fragile X syndrome, and spinal muscular atrophy is available,2 and in the future we may be able to screen for a vastly expanded number of diseases. The Royal Australian and New Zealand College of Obstetricians and Gynaecologists has recently released a position statement to recommend that all women, either before pregnancy or in the first trimester, should be offered carrier screening for inherited conditions.3 Reproductive carrier screening should be a routine part of pregnancy care and should be considered a health care right.

R John Massie · Martin B Delatycki

Without improved practices and policy to guide the engagement and inclusion of Indigenous Australians in biobanks, the full health benefits provided by the genomic era will not be shared equitably

Imogen Elsum · Callum McEwan · Emma E Kowal · Yvonne Cadet‐James · Margaret Kelaher · Lynn Woodward